Vitamin D may help reduce the risk of cardiovascular and other chronic diseases. Large clinical trials are currently underway to formally determine whether vitamin D treatment will lower the risks of cardiovascular diseases, fractures, and cancer. Pending results of clinical trials, laboratory testing and treatment for vitamin D deficieny have become widespread in clinical practice. Limited data are available regarding which individuals are most likely to respond to vitamin D treatment, hindering clinical evaluation and limiting interpretation of ongoing trials. The goal of this application is to identify individual-lvel characteristics (genetic and biomarker) that inform the biologic response to vitamin D treatment. To accomplish the goal we will randomly assign 1,600 participants from the Multi-Ethnic Study of Atherosclerosis to 16-weeks of vitamin D3 (2000 IU daily) or matching placebo in a 3:1 ratio. We will determine whether the biological effects of vitamin D3 treatment are modified by genetic polymorphisms in vitamin D metabolic pathways and/or by novel biochemical measures of baseline vitamin D status. Findings from the studies proposed in this application could augment the interpretation of ongoing vitamin D clinical trials and catalyze a precision medicine approach aimed at maximizing the benefits of vitamin D therapy while potentially reducing harm and substantially decreasing costs.